EP1235803A1 - Composes d'uree presentant une activite antagoniste du recepteur muscarinique - Google Patents

Composes d'uree presentant une activite antagoniste du recepteur muscarinique

Info

Publication number
EP1235803A1
EP1235803A1 EP00982493A EP00982493A EP1235803A1 EP 1235803 A1 EP1235803 A1 EP 1235803A1 EP 00982493 A EP00982493 A EP 00982493A EP 00982493 A EP00982493 A EP 00982493A EP 1235803 A1 EP1235803 A1 EP 1235803A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
compound
group
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP00982493A
Other languages
German (de)
English (en)
Other versions
EP1235803B1 (fr
Inventor
Mathai Mammen
David Oare
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innoviva Inc
Original Assignee
Theravance Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theravance Inc filed Critical Theravance Inc
Priority to EP04012859A priority Critical patent/EP1457488B1/fr
Publication of EP1235803A1 publication Critical patent/EP1235803A1/fr
Application granted granted Critical
Publication of EP1235803B1 publication Critical patent/EP1235803B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems

Definitions

  • a receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell
  • extracellular receptors within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
  • a ligand is a binding partner for a specific receptor or family of receptors.
  • a ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
  • the G-proteins when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).
  • Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M réelle M 2 , M 3 , M 4 and M 5 ) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I. et al., Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E.C., et al., Annu. Rev.
  • the smooth muscle is composed largely of M 2 and M 3 receptors
  • cardiac muscle is composed largely of M 2 receptors
  • salivary glands are largely composed of M 3 receptors.
  • muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs, 1997, 6(10), 1395-1411; Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(1 1), 1 105-1 108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).
  • diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic co
  • a number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases.
  • oxybutynin is being used for the treatment of urinary urge incontinence
  • dicyclomine is being used for the treatment of irritable bowel syndrome.
  • these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis.
  • novel muscarinic receptor antagonists There is currently a need for novel muscarinic receptor antagonists.
  • the invention is directed to urea derivatives that are muscarinic receptor antagonists and agonists and that are useful in the treatment and prevention of diseases mediated by muscarinic receptors (e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like).
  • diseases mediated by muscarinic receptors e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
  • the invention provides a compound of the invention which is a compound of Formula (I):
  • L is a group of formula (a):
  • A is an aryl or a heteroaryl ring
  • B" is -NR a - wherein R a is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
  • R 1 is hydrogen or alkyl
  • R 2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii):
  • n is an integer of from 1 to 4; n 2 is an integer of from 1 to 3; V is -CH-, -O-, -S(O)n 3 - (where n 3 is an integer of from 0 to 2), or -NR 4 -
  • R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl
  • Het is a heteroaryl ring which optionally attaches (a) to a linker;
  • R 3 is hydrogen, alkyl, amino, substituted amino, -OR a (where R a is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
  • R 5 is hydrogen, alkyl, amino, substituted amino, -OR b (where R b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
  • R 6 , R 7 , and R 8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino
  • K is a bond or an alkylene group
  • K" is a bond, -C(O)-, -S(O) n4 - (where n 4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker; provided that at least one of the R 5 , R 6 , R 7 , R 8 , "Het", heterocycloamino or heteroarylamino groups attaches (a) to a linker; X is a linker; 1- 2 is a group selected from a group consisting of:
  • D is alkylene
  • D is -NR 31 R 32 , -N + (R 33 R 34 R 35 ) or -OR 32 where R 31 , R 33 , and R 34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R 32 and R 35 represent a covalent bond attaching (b) to a linker;
  • R 27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R 28 is hydrogen, halo, nitro, cyan
  • R 29 and R 30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or one of R 27 , R 28 , R 29 , or R 30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group;
  • n is an integer of from 1 to 7; n 12 is 0 to 7;
  • F is -NR 40 -, -O-, -S-, or -CHR 41 - (wherein R 40 and R 41 are, independently of each other, hydrogen, alkyl, or substituted alkyl);
  • F is a covalent bond, -OR 43 , -NR 42 R 43 , or -N + R 43 R 4 R 45 wherein R 42 is hydrogen or alkyl, R 44 and R 45 are alkyl, and R 43 is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
  • R 36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R 37 is hydrogen, alkyl,
  • R 38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R 38 and R 43 attaches (c) to a linker;
  • R 39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and (iii) a group of formula (d) or (e):
  • R 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;
  • R 47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or -COOR 50 where R 50 is alkyl; or
  • R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • one or more e.g. 1, 2, 3, or 4
  • R 48 is a covalent bond that attaches the (d) or the (e) to a linker; and R 49 is alkyl; or a pharmaceutically acceptable salt; or prodrug thereof.
  • X is a group of formula:
  • X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S)-, -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below;
  • Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
  • Y a and Y b at each separate occurrence are selected from the group consisting of -O-, -C(O)-, -OC(O)-, -C(O
  • a preferred compound of the invention is a compound of formula (IVa):
  • X, and I- ⁇ have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
  • the invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof.
  • the invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal.
  • Applicant has discovered that urea compounds of the present invention are metabolically more stable than compounds lacking such a urea functionality.
  • compounds of the present invention have longer metabolic half -lives and/or longer duration of action in vivo, which can reduce the dose required for administration or can reduce the likelihood of the generation of unwanted metabolites.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, rc-propyl, wo-propyl, n-butyl, iso- butyl, n-hexyl, «-decyl, tetradecyl, and the like.
  • substituted alkyl refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -O-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms.
  • This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • substituted alkylene refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamin
  • substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocydic or heteroaryl groups fused to the alkylene group.
  • fused groups contain from 1 to 3 fused ring structures.
  • alkylaminoalkyl refers to the groups R a NHR b - where R a is alkyl group as defined above and R b is alkylene, alkenylene or alkynylene group as defined above.
  • R a is alkyl group as defined above
  • R b is alkylene, alkenylene or alkynylene group as defined above.
  • Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino- 1 , 1 -dimethylbutyn- 1 -yl, 4- ethylaminobutyn-1-yl, and the like.
  • alkaryl refers to the groups -alkylene-aryl and - substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • alkoxy refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-p ⁇ opoxy, n-butoxy, tert-butoxy, _.ec-butoxy, n-pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, and the like.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • haloalkoxy refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene- O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), n-propylene-wo-propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -O-C(CH 3 ) 3 ), and the like.
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene- S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Preferred alkylthioalkoxy groups are alkylene-S- alkyl and include, by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), n-propylene-wo-thiopropoxy
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • substituted alkenyl refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamin
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation.
  • substituted alkenylene refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxya
  • substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocydic or heteroaryl groups fused to the alkenylene group.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, substituted
  • alkynylene refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
  • Preferred alkynylene groups include ethynylene (-C ⁇ C-), propargylene (-CH 2 C ⁇ C-), and the like.
  • substituted alkynylene refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxy
  • acyl refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl- C(O , cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic- C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocydic are as defined herein.
  • acylamino or "a inocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocydic or where both R groups are joined to form a heterocydic group (e.g., mo ⁇ holino) wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocydic are as defined herein.
  • aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocydic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocydic are as defined herein.
  • aminoacyloxy or “alkoxycarbonylamino” refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocydic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocydic are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, aminoacyloxy, oxyacylamin
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3- phenylene, 1 ,4-phenylene, 1 ,2-naphthylene and the like.
  • amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocydic provided that both R's are not hydrogen.
  • carboxyalkyl or “alkoxycarbonyl” refers to the groups “-C(O)O-alkyl", “-C(O)O-substituted alkyl", “-C(O)O-cycloalkyl", “-C(O)O- substituted cycloalkyl", “-C(O)O-alkenyl”, “-C(O)O-substituted alkenyl", “-C(O)O-alkynyl” and "-C(O)O-substituted alkynyl” where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamin
  • cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxy
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryl
  • Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • heteroarylkyl refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • heteroarylene refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1 ,2-quinolinylene, 1 ,8-quinolinylene, 1 ,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like.
  • heterocycle or “heterocydic” or refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heterocydic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamino
  • nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinohne, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, mo ⁇ holine, tetrahydrofuranyl, tetrahydrothioph
  • heterocyclooxy refers to the group heterocyclic-O-.
  • thioheterocyclooxy refers to the group heterocyclic-S-.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-mo ⁇ holino, 2,5-mo ⁇ holino and the like.
  • Heteroarylamino means a 5 membered aromatic ring wherein one or two ring atoms are N, the remaining ring atoms being C.
  • the heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alken
  • Heterocycloamino means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl].
  • heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, mo ⁇ holino, piperazino, indolino, or thiomo ⁇ holino.
  • heterocycloamino also includes, quinuclidine, l-azabicyclo[2.2.1]heptyl, l-azabicyclo[3.2.1]octyl and the derivatives thereof.
  • oxyacylamino or “aminocarbonyloxy” refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocydic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocydic are as defined herein.
  • spiro-attached cycloalkyl group refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
  • thiol refers to the group -SH.
  • thioalkoxy or "alkylthio” refers to the group -S-alkyl.
  • substituted thioalkoxy refers to the group -S -substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
  • thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • any of the above groups which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non- feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • pharmaceutically-acceptable salt refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable.
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri (substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, substituted cycloalkyl amines, substituted
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocydic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(w_.-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, mo ⁇ holine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /? -toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically-acceptable cation refers to the cation of a pharmaceutically-acceptable salt.
  • protecting group refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzyli ine, phenacyl, t-butyl- diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like.
  • Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product.
  • the term "optional” or “optionally” means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • inert organic solvent or “inert organic solvent” means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like.
  • the solvents used in the reactions described herein are inert solvents.
  • treatment refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes:
  • pathologic condition which is modulated by treatment with a ligand covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be usefully treated by a compound of the invention.
  • disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
  • therapeutically effective amount refers to that amount of a compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • linker identified by the symbol 'X' refers to a group or groups that covalently attaches L, and I ⁇ . Additionally, the linker can be either a chiral or achiral molecule.
  • linker does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
  • Pro-drugs means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • a preferred value for A is phenyl or pyridine
  • a preferred value for R 1 is hydrogen methyl, or ethyl. Another preferred value for R 1 is hydrogen.
  • R z is pyrrolyl, pyridinyl, or imidazolyl.
  • R 2 is phenyl
  • V is -CH- or -NR 4 - (wherein R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl).
  • R 3 is hydrogen or alkyl
  • R 5 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker
  • R 5 is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino.
  • R 6 , R 7 , and R 8 independent of each other is hydrogen, alkyl, nitro, hydroxy, or amino.
  • a preferred value for K is alkylene having from 1 to 10 carbon atoms.
  • a preferred value for K is alkylene having from 1 to 5 carbon atoms.
  • a preferred value for K is a bond or a methylene group.
  • a preferred value for K" is a bond.
  • a preferred value for R a is hydrogen.
  • a preferred value for B is a heterocycloamino group which attaches (a) to a linker.
  • Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (1):
  • n 22 is 0 or 1 ;
  • R 53 and R 54 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker;
  • R 55 is alkyl, alkenyl or alkynyl; and W b is -N(O)n 23 or -N + -R 56 where n 23 is 0 or 1, and R 56 is alkyl, alkenyl, alkynyl, or aralkyl, or a covalent bond attaching (a) to a linker; provided that a carbon other than a bridge head carbon is bonded to B".
  • B is a ring represented by the following general formulae:
  • a more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.
  • Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.
  • Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.
  • B is quinuclidine, l-azabicyclo[2.2.1]- heptyl, or l-azabicyclo[3.2.1]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to B".
  • a preferred value for D" is-(CH 2 )n 43 - where n 43 is an integer of from 1-10, preferably 2-8, more preferably 2-4. Another preferred value for n 43 is an integer of from 3-10.
  • a preferred value for D is -NR 31 R 32 or -N + (R 33 R 34 R 35 )M " where R 31 , R 33 , and
  • R 34 are, independently of each other, hydrogen or methyl, and R 32 and R 35 represent a covalent bond attaching (b) to a linker. More preferably R 31 , R 33 , and R 34 methyl, . and R 32 and R 35 represent a covalent bond attaching (b) to a linker.
  • a preferred value for R 27 is hydrogen.
  • a preferred value for R 28 is hydrogen.
  • a preferred value for R 29 and R 30 independently is hydrogen; or one of R 27 , R 28 , R 29 , or R 30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group.
  • a preferred value for n ⁇ is 1.
  • a preferred value for n 12 is 6.
  • a preferred value for F is -O-.
  • a preferred value for F' is a covalent bond, -OR 43 , -NR 42 R 43 wherein R 42 is hydrogen or alkyl, or -N + (R 43 R 44 R 45 ) wherein R 44 and R 45 are alkyl, and R 43 is a covalent bond attaching (c) to a linker.
  • a preferred value for F" is -O-, -NH-, N(CH 3 )- or -N(CH 3 ) 2 -
  • a more preferred value for F' is -NH-, N(CH 3 )- or -N(CH 3 ) 2 - wherein the nitrogen atom attaches (c) to a linker.
  • a preferred value for R 36 is hydrogen.
  • R 37 is ortho to the -(CHR 38 )- group and is hydrogen or alkoxy. More preferably R 37 is ortho to the -(CHR 38 )- group and is methoxy.
  • R 38 is hydrogen.
  • R 39 is hydrogen.
  • Lj is a group of formula (d) wherein: R 46 is alkyl or substituted alkyl; R 47 is alkyl, substituted alkyl, or heterocycle; or R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle.
  • L ⁇ is a group of formula A1-A241 as shown in the following table.
  • L j is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L ⁇ .
  • I_ 2 can also be a group of formula A301-A439 as shown in the following table.
  • L ⁇ is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of I_ 2 .
  • L ⁇ can also be a group of formula A501-A523 as shown in the following table.
  • 1 ⁇ is preferably linked to X through a non-aromatic nitrogen atom of l ⁇ .
  • a more preferred value for 1- 2 is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.
  • a preferred value for X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
  • X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, or 4) in the alkylene group is optionally replaced with -O-; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1 , 2, 3, or 4).
  • Another preferred value for X is an alkylene group having from 6 to 15 carbons atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, 4) in the alkylene group is optionally replaced with -O-; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4).
  • Another preferred value for X is is nonane- 1 ,9-diyl, octane- 1 ,8-diyl, propane- 1,3-diyl, 2-hydroxypropane-l,3-diyl, or 5-oxa-nonane-l,9-diyl.
  • phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is selected from formula (i) and (iii); and wherein K" is a bond or methylene.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is formula (i); R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K" is a bond or methylene.
  • a preferred group of compounds of formula (I) are compounds wherein R 2 is formula (iii); R 6 , R 7 , and R 8 are each hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and K" is a bond or methylene.
  • a preferred group of compounds are compounds of formula (I) wherein R 46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R 47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or -COOR 50 where R 50 is alkyl; or R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle.
  • a preferred group of compounds are compounds of formula (I) wherein L ⁇ is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, hetero
  • a more preferred group of compounds are compounds of formula (I) wherein X__ is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • a preferred group of compounds are compounds of formula (I) wherein L ⁇ is a group of formula (d) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • a preferred group of compounds are compounds of formula (I) wherein 1 ⁇ is a group of formula (d) wherein at least one of R 46 and R 47 individually, or R 46 and R 47 taken together, is a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • a basic nitrogen atom e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7.
  • a preferred group of compounds are compounds of formula (I) wherein ⁇ is a group of formula (d) wherein R 46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R 47 is alkyl, substituted alkyl, acyl, or -COOR 50 .
  • a preferred group of compounds are compounds of formula (I) wherein L 2 is a group of formula (d) wherein R 46 is alkyl that is substituted by a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • a basic nitrogen atom e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
  • a preferred group of compounds are compounds of formula (I) wherein L j is a group of formula (d) wherein R 46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamino, NR a R b , wherein R a and R b may be the same
  • a preferred group of compounds are compounds of formula (I) wherein L ⁇ is a group of formula (d) wherein R 46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocydic, heterocyclooxy, hydroxyamino,
  • a preferred group of compounds are compounds of formula (I) wherein L ⁇ is a group of formula (d) wherein R 46 is 3-piperidinyl, 4-piperidinyl, or 3- pyrrolidinyl, which R 46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxya
  • a preferred group of compounds are compounds of formula (I) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocydic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alky
  • a preferred group of compounds are compounds of formula (I) wherein R 46 and R 47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. l-aza-12-crown-4, l-aza-15-crown-5, or 1 -aza- 18-crown-6).
  • aza-crown ether e.g. l-aza-12-crown-4, l-aza-15-crown-5, or 1 -aza- 18-crown-6.
  • a preferred group of compounds of formula (I) are compounds wherein: A is an aryl or a heteroaryl ring; B" is -NRa- wherein Ra is hydrogen, alkyl, or substituted alkyl; R 1 is hydrogen or alkyl; R 2 is selected from a group consisting of formula (i), (ii), (iii), or "Het”: wherein: is an optional double bond; n, is an integer of from 1 to 4; n 2 is an integer of from 1 to 3; V is -CH-, -O-, -S(O)n 3 - (where n 3 is an integer of from 0 to 2), or -NR 4 - (wherein R 4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); "Het” is a heteroaryl ring which optionally attaches the ligand to a linker; R 3 is hydrogen, alkyl, amino, substituted amino, -OR a (where R a is hydrogen,
  • a preferred compound of formula (I) is a compound of Formula (la):
  • A, R 1 , R 2 , K, K", B, X, R 46 and R 47 are as defined herein.
  • a preferred group of compounds is that wherein A is phenyl or pyridine; and K and K" are bond.
  • the invention also provides a compound of formula (IV):
  • j is an organic group comprising at least one (e.g. 1, 2, 3, or 4) primary, secondary, or tertiary amines.
  • the amine of L j should be basic, having a pH of at least about 5, and preferably at least about 6, more preferably at least about 7.
  • the nature of the group 1 ⁇ is not critical provided the compound has suitable properties (e.g. solubility, stability, and toxicity) for its intended use (e.g. as a drug or as a pharmacological tool).
  • the group ⁇ will have a molecular weight below 500 and preferably below about 300.
  • the group L j preferably comprises 5 or fewer hydrogen bond donors (e.g.
  • the nitrogen of B shown in formula (IV) is separated from an amine of the group X__ by about 15 angstroms to about 75 angstroms (based on conventionally acceptable bond lengths and angles). More preferably, the nitrogen of B is separated from an amine of the group ⁇ _ by about 25 angstroms to about
  • Preferred compounds of formula (IV) also have a log D between about -3 and about 5. Using the above parameters, one skilled in the art can readily determine compounds of formula (IV) possessing the desired properties for an intended use. GENERAL SYNTHETICSCHEMES
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St.
  • Such materials may be characterized using conventional means, including physical constants and spectral data.
  • process conditions i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • a compound of Formula (I) is prepared by covalently attaching one equivalent of a compound of formula 1 with a compound of formula 2 where X is a linker as defined herein, FG 1 is a functional group, FG 2 is a functional group that is complimentary to FG 1 , PG is a protecting group, and FG 2 PG is a protected functional group, to give an intermediate of formula (II).
  • Deprotection of the functional group on the linker, followed by reaction of resulting compound 3 with one equivalent of compound 4 then provides a compound of Formula (I).
  • the reaction conditions used to link compounds 1 and 4 to compound 2 and 3 depend on the nature of the functional groups on compounds 1, 2, 3 and 4 which in turn depend on the type of linkage desired. Examples of the functional groups and the reaction conditions that can be used to generate a specific linkage is described below.
  • First Reactive Group Second Reactive Group Linkage carboxyl amine amide sulfonyl halide amine sulfonamide hydroxyl alkyl/aryl halide ether hydroxyl isocyanate urethane amine epoxide ⁇ -hydroxyamine amine alkyl/aryl halide alkylamine hydroxyl carboxyl ester
  • Suitable dihydroxyl and dihalo starting materials useful for incorporating a group X into a compound of the invention are shown in the following table.
  • an alcohol is reacted with a ligand bearing a leaving group to provide an ether bond
  • a dihalo compound is preferably reacted with an amine of the ligand to form a subatituted amine.
  • a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be readily coupled to the linker.
  • functional group such as an amino, hydroxyl, thiol or carboxyl group and the like.
  • a compound of formula (a) wherein A is phenyl, pyridyl, and the like can be prepared as described in EP 747 355 and as described by Naito, R. et al., Chem. Pharm. Bull., 1998, 46(%), 1286.
  • a compound of formula (I) wherein L, comprises a nitrogen that is bonded to X can be prepared by alkylating a corresponding compound of formula L,-H wherein -H is bound to the nitrogen, with a corresponding compound of R.-X-L 2 wherein X and 1- ⁇ have any of the values defined herein and R a is a suitable leaving group.
  • Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York.
  • R a can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4- tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • the invention provides a method for preparing a compound of formula (I) wherein L, comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L r H with a compound of R ⁇ X-L ⁇ wherein X and I_ 2 have any of the values defined herein and R a is a suitable leaving group.
  • the invention also provides a compound of formula L,-H wherein L, has any of the values defined herein.
  • L has any of the values defined herein.
  • the following compounds are preferred compounds of formula L,-H:
  • the invention also provides a compound of formula R.-X-L 2 wherein X, and I_ 2 have any of the values defined herein and R a is a suitable leaving group.
  • the compound of formula L,-H can also be alkylated by treatment with an aldehyde of formula L j -V-CHO (wherein -V-CH 2 - is equivalent to -X-), under reductive alkylation conditions.
  • Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • the invention provides a method for preparing a compound of formula (I) wherein L, comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L r H with a compound of formula L ⁇ -V-CHO (wherein -V-CH 2 - has any of the values for -X- described herein).
  • a compound of formula (I) wherein L ⁇ comprises a nitrogen that is bonded to X can be prepared by alkylating a corresponding compound of formula L j -H wherein -H is bound to the nitrogen, with a corresponding compound of L,-X-R a wherein X and L j have any of the values defined herein and R a is a suitable leaving group.
  • Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York.
  • R a can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4- tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
  • the invention provides a method for preparing a compound of formula (I) wherein I- ⁇ comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L j -H with a compound of L,-X-R a wherein X and L, have any of the values defined herein and R a is a suitable leaving group.
  • the compound of formula L ⁇ -H can also be alkylated by treatment with an aldehyde of formula L,-V-CHO (wherein -V-CH 2 - is equivalent to -X-), under reductive alkylation conditions.
  • aldehyde of formula L,-V-CHO wherein -V-CH 2 - is equivalent to -X-
  • Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).
  • the invention provides a method for preparing a compound of formula (I) wherein X comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L ⁇ -H with a compound of formula L,-V-CHO (wherein -V-CH 2 - has any of the values for -X- described herein).
  • the invention provides a method for preparing a compound of formula (I) comprising deprotecting a corresponding compound of formula (I) that bears one or more protecting groups.
  • the invention also provides an intermediate compound of formula (I) that bears one or more protecting groups.
  • Combinatorial Synthesis Compounds of formula (I) can conveniently be prepared using combinatorial synthesis methods (e.g. solid phase and solution phase combinatorial synthesis methods) that are known in the art.
  • combinatorial synthesis methods e.g. solid phase and solution phase combinatorial synthesis methods
  • compounds of formula (I) can be prepared using combinatorial methods like those escribed in International Patent Application Publication Number WO 99/64043.
  • the compounds of this invention are muscarinic receptor antagonists or agonists.
  • a preferred sub-groug of compounds of the invention are M 2 muscarinic receptor antagonists.
  • the compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, hyper salvation syndromes, and the like.
  • the ability of the compounds of formula (I) to inhibit a muscarinic receptor may be demonstrated using a variety of in vitro assays and in vivo assays known in the field, or may be demonstrated using an assay described in biological examples 1-6 below.
  • compositions When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intravesicular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, usually about 0.1 to about 500 mg, more usually about 1 to about 50 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of Formula (I) above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Example 1 The intermediate compound of formula IB was prepared as follows.
  • Biphenyl-2-isocynate (50g, 256 mmol) was dissolved in 400 mL anhydrous acetonitrile in a 2L rbf at room temperature. After cooling to 0 C using an ice bath, a solution of 4-amino-N-benzylpiperidine (48.8g, 256 mmol) dissolved in 400mL anhydrous acetonitrile was added over 5 minutes. Precipitate was observed immediately. After 15 minutes, an additional 600mL anhydrous acetonitrile was added to permit stirring of the viscous solution for 12h at 35 C. The solids were filtered, and washed with cold acetonitrile then dried under vacuum, yielding a colorless solid (lOOg, 98%). This material was characterized by ⁇ -NMR, 13 C- NMR and MS.
  • Example 1 Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • Example 2 A tablet Formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50° to 60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • Example 7 Suspensions, each containing 50 mg of medicament per 5.0 mL dose are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a formulation may be prepared as follows:
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.
  • a formulation may be prepared as follows:
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference in its entirety.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Example 1 M 2 Muscarinic Receptor In Vitro Binding Assay The M 2 muscarininc receptor binding activity of compounds of the invention was tested as follows. SF9 cell membranes containing human M 2 muscarinic receptor was obtained from NEN (Boston, MA). In 96-well microtiter plates, eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 ⁇ M (4x the final concentration). To 100 ⁇ l of compound dilution was added 150 ⁇ L M 3 receptor membrane preparation in PBS/1. OmM MgCl 2 /pH 7.4. 50 ⁇ l of 3.2 nM 3H-N-methylscopolamine radioligand was added.
  • Representative compounds of the invention were found to have pK b values of greater than 6, and to have IC 50 values of less than about 50 ⁇ m.
  • a similar protocol was used to measure Ml, M3, M4 and M5 human muscarinic receptor activity.
  • Example 2 Rat Heart Muscarinic Receptor In Vitro Binding Assay Tissue (rat heart) muscarininc receptor binding activity of compounds of the invention was tested as follows.
  • Rat heart tissue was typically prepared as follows. 25 ⁇ l of ice cold buffer (20mM HEPES, lOOmM NaCl/lOmM MgCl 2 at pH 7.5 with "Complete" protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube. To the tube was then added 2 g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homogenized using a Polytron homogenizer (setting 22, 15 seconds x2), and then transferred back to the oakridge tube, and centrifuged for 10 minutes at 1500 g.
  • ice cold buffer (20mM HEPES, lOOmM NaCl/lOmM MgCl 2 at pH 7.5 with "Complete" protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube.
  • To the tube was then added 2 g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homo
  • the supernatant was removed and then centrifuged for 20 minutes at 45000 g.
  • the supernatant was removed and the pellet resuspended in 5 mL buffer and transferred to a wheaton glass cylinder.
  • This material was then homogenized using a Potter type glass teflon homogenizer with 7-8 passes.
  • the material was then transferred to an oakridge tube and the total volume was brought up to 25 mL.
  • This material was then centrifuged for 20 minutes at 45000 g, and the pellet resuspended in 2 mL buffer using 2 passes of a teflon homogenizer, and stored at -80 °C until used.
  • a protocol similar to that used for cloned receptor binding was used: Eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 ⁇ M (4x the final concentration). To 50 ⁇ l of compound dilution in a 96- well assay plate was added an appropriate amount of rat heart membrane (usually 12.5 ⁇ l of membrane prep in 87.5 ⁇ l of 20mM HEPES, lOOmM NaCl/lOmM MgCl 2 at pH 7.5). The amount of membrane added depends in general on the results of signal optimization, and ranges from 6.25-12.5 ⁇ l. Last, 50 ⁇ l of 2.12 nM 3H-N-methylscopolamine radioligand was added.
  • the total volume in each well was 200 ⁇ l.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 min., and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 h at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200 ⁇ l PBS.
  • About 40 ⁇ l of scint was added to each well and then the plate was allowed to sit at room temperature for 18 h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 min., per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have pK b values of greater than 6, and to have IC 50 values of less than about 50 ⁇ m.
  • Example 3 Rat Bladder M 3 In Vitro Binding Assay Bladder was comprised of both M 2 and M 3 muscarinic receptors. The ratio was typically 4: 1 M 2 :M 3 . In order to measure binding of test compounds to one of M 2 or M 3 , the other was blocked with a reversible ligand that binds selectively to that receptor. The following example illustrates the procedure for M 3 bladder binding.
  • Membranes from rat bladder were prepared in a similar fashion to that used to isolate heart membrane above. Eight serial five-fold dilutions were prepared with the compound to be assayed in compound dilution buffer (20 mM HEPES/ 1 OOmM NaCl/1 OmM MgCl 2 /4 ⁇ M Methoctramine); the highest concentration was typically 4 ⁇ M (4x the final concentration). The concentration of methoctramine was sufficient to block >99% of the M2 receptor in bladder, but less than 40% of the M 3 receptor in bladder.
  • rat heart membrane To 50 ⁇ l of compound dilution in a 96- well assay plate was added an appropriate amount of rat heart membrane (usually 25 ⁇ l of membrane prep in 75 ⁇ l of 20 mM HEPES, 100 mM NaCl/10 mM MgCl 2 at pH 7.5). The amount of membrane added depended in general on the results of signal optimization, and ranged from 12.5-25. Last, 50 ⁇ l of 2.12 nM . 3H-N-methylscopolamine radioligand in compound dilution buffer was added. The total volume in each well was 200 ⁇ l. The final concentration of methoctramine was 2 ⁇ M.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 mins., and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate was then transferred to the filter plate, and washed three times using 200 ⁇ l PBS. About 40 ⁇ l of scint was added to each well, the plate was allowed to sit at room temperature for 18h, and then counted using a Packard Topcount NXT.
  • Counting was typically performed for 1 minute per well using a standard protocol on the Packard counter. The data was fit to normal isotherms and values for inhibition constants were extracted. Representative compounds of the invention were found to have IC 50 values of less than about 500 ⁇ m. A similar procedure was used to measure binding at bladder M 2 , but in this case, 2 ⁇ M Darifenacin was used to block >99% of the M 2 receptor, but minimal M 3 receptor.
  • Example 4 Ex Vivo Rat Bladder Contraction Assay The ability of the test compound to inhibit cholinergically stimulated bladder contraction was tested as follows. Male Sprague-Dawley rats weighing 250 - 300 g are killed by CO 2 overdose. The bladder was removed and placed in a petri dish containing Krebs-Henseleit solution at room temperature. The apex and dome areas of the bladder were discarded and the remaining tissue cut into longitudinal strips (4 from each rat). The strips were mounted in an organ bath containing Krebs-Henseleit solution at 37 °C, under a resting tension of 0.5 g. The tissues were allowed to equilibrate for 60 min., (washes at 0, 30 and 60 min.). Tension was readjusted to 1 g as necessary.
  • a cumulative concentration response curve to carbachol (10-8 M to 10-5 M (e.g.) in 3-fold increments) was constructed in each tissue. Tissues were then washed every 5 min., for 30 min., and tension readjusted to 1 g. After additional 30 min., muscarinic antagonist (typically 1x10-7 M) or vehicle was added. Thirty minutes after antagonist or vehicle addition, a cumulative concentration response curve to carbachol (10-8M to 10-3M (e.g.)) was constructed. Data from each concentration response curve was expressed as a percentage of the maximum contraction to carbachol. The EC 50 values were calculated. The concentration-ratios were calculated taking into account any spontaneous shift in the control tissue. For competitive antagonists, the pKb value was calculated using the following equation: pKb -log [antagonist concentration]
  • Rat Salivation Assay Male Sprague-Dawley rats weighing 250 - 300 g were anesthetized with pentobarbital (60 mg/kg i.p.). Rats were placed on a heated blanket under a 20 degree incline. A swab was placed in the rat's mouth. Muscarinic antagonist or vehicle was administered i.v. via the tail vein. After 5 min., oxotremorine (0.3 mg/kg) was administered s.c. The swab was discarded and replaced by a pre- weighed swab. Saliva was then collected for 15 min. After 15 min., the swab was weighed and the difference in its weight was used to calculate the antisecretory potency of the antagonists. The data was fit to normal isotherms and ID 50 values were extracted.
  • Example 6 In Vivo Bladder Assay Male Sprague-Dawley rats weighing 250 - 300 g were anesthetized with urethane (1.3 g/kg, i.p.), inactin (25 mg/kg, i.p.), and xylazine (4 mg, i.p.). The jugular (or femoral) vein was isolated and ligated and a small incision was made in the vein distal to the ligation. A catheter (micro-Renathane tubing (0.014 mm ID x 0.033 mm OD) filled with saline was inserted into the vein and secured into place with suture thread. The trachea was isolated and placed in a small hole between two of the rings.
  • urethane 1.3 g/kg, i.p.
  • inactin 25 mg/kg, i.p.
  • xylazine 4 mg, i.p.
  • Tubing (1.57 mm ID x 2.08 mm OD) was inserted into the trachea and tied into place with suture thread. The incision was closed leaving the tubing exposed. The tracheotomy was to prevent the animal from asphyxiating on his own saliva following oxotremorine administration.
  • the stomach was shaved and then cleaned with ethanol. A midline sagital incision was made in the skin and muscle layers of the lower stomach.
  • the bladder was exposed and the saline filled cannula (22-gauge needle attached to a pressure transducer with PE 90 tubing) was inserted into the apex of the bladder to the most distal part of the bladder. The bladder was placed back into the peritoneal cavity.
  • the bladder was emptied manually by disconnecting the cannula and allowing the contents to flow out until the bladder was approximately 1 cm in diameter. The incision was closed with suture thread, first the muscle layer, then the skin in order to keep the bladder moist and warm. The exposed portion of the cannula to the skin surface was sutured to hold it in place. After 15 min. oxotremorine (0.3 mg/kg, SC, baseweight) was injected. After 10 min., (or until baseline stabilized) a test compound or a reference standard was injected with a dose equivalent to 0.005 - 0.01 mg kg, IV, baseweight of atropine that produced a 30-70% decrease in intraluminal pressure. After 5 min., a high dose of atropine 0.1 mg/kg was injected, i.v., to establish the true 100% inhibition point.
  • oxotremorine 0.3 mg/kg, SC, baseweight
  • the oxotremorine response (zero inhibition) was determined by measuring the mean pressure 1 minute prior to the antagonist injection. Then, to assess antagonist inhibition, mean pressure was measured beginning at 1 minute and ending 2 minutes after antagonist administration. If the pressure had not leveled off after 1 minute, a wait was initiated until it was stable and then a 1 -minute sample of the mean was taken. Lastly, to determine the true 100% inhibition point, the mean pressure was measured beginning 1 minutes and ending 2 minutes after the high dose atropine challenge. The percent inhibition by the antagonist can be determined by the ratio of the decrease from the zero to 100% values.
  • the formula is: oxotremorine mean - treatment mean *100 oxotremorine mean - atropine mean.
  • the activity of a compound of the invention on other tissues can be determined using screening protocols that are known in the art. For example, an assessment of increased locomotor activity (assay for CNS penetration) can be carried out as described by Sipos ML, et al., (1999) Psychopharmacology 147(3):250-256; an assessment of the effects of a compound on gastrointestinal motility can be carried out as described by Macht DI, and Barba-Gose J (1931) J Am Pharm Assoc 20:558-564; an assessment of the effects of a compound on pupil diameter (mydriasis) can be carried out as described by Parry M, Heathcote BV (1982) Life Set 31:1465-1471; and an assessment of a compounds effects on urinary bladder in dog can be carried out as described by Newgreen DT, et al. (1996) J Urol 155:600A.
  • Preferred compounds of the invention may display selectivity for one or more tissues over other tissues.
  • compounds of the invention that are useful for treating urinary incontinence may show higher activity in the assay of Example 6 than in the assay of Example 5.
  • Preferred compounds useful for treating urinary incontinence and irritable bowel syndrome have greater antagonist activity at the M 2 receptor than at the M 3 receptor or the other muscarinic receptors.
  • Preferred compounds useful for treating unwanted salivation have greater antagonist activity at the M 3 receptor than at the M 2 receptor or the other muscarinic receptors.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne des composés d'urée lesquels sont des antagonistes et des agonistes du récepteur muscarinique, des compositions pharmaceutiques contenant ces composés ainsi que des méthodes de préparation desdits composés.
EP00982493A 1999-12-07 2000-12-07 Composes d'uree presentant une activite antagoniste du recepteur muscarinique Expired - Lifetime EP1235803B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04012859A EP1457488B1 (fr) 1999-12-07 2000-12-07 Produits intermédiaires pour la préparation de dérivés de l'urées présentant une activité antagoniste du recepteur muscarinique

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US45617099A 1999-12-07 1999-12-07
US456170 1999-12-07
PCT/US2000/033155 WO2001042213A1 (fr) 1999-12-07 2000-12-07 Composes d'uree presentant une activite antagoniste du recepteur muscarinique

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP04012859A Division EP1457488B1 (fr) 1999-12-07 2000-12-07 Produits intermédiaires pour la préparation de dérivés de l'urées présentant une activité antagoniste du recepteur muscarinique

Publications (2)

Publication Number Publication Date
EP1235803A1 true EP1235803A1 (fr) 2002-09-04
EP1235803B1 EP1235803B1 (fr) 2004-07-14

Family

ID=23811737

Family Applications (2)

Application Number Title Priority Date Filing Date
EP00982493A Expired - Lifetime EP1235803B1 (fr) 1999-12-07 2000-12-07 Composes d'uree presentant une activite antagoniste du recepteur muscarinique
EP04012859A Expired - Lifetime EP1457488B1 (fr) 1999-12-07 2000-12-07 Produits intermédiaires pour la préparation de dérivés de l'urées présentant une activité antagoniste du recepteur muscarinique

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP04012859A Expired - Lifetime EP1457488B1 (fr) 1999-12-07 2000-12-07 Produits intermédiaires pour la préparation de dérivés de l'urées présentant une activité antagoniste du recepteur muscarinique

Country Status (27)

Country Link
US (3) US6635764B2 (fr)
EP (2) EP1235803B1 (fr)
JP (1) JP2003516391A (fr)
KR (1) KR100748150B1 (fr)
CN (1) CN1271054C (fr)
AT (2) ATE439345T1 (fr)
AU (1) AU782232B2 (fr)
BR (1) BR0015963A (fr)
CA (1) CA2392030C (fr)
CZ (1) CZ20021830A3 (fr)
DE (2) DE60042762D1 (fr)
EA (1) EA006437B1 (fr)
ES (3) ES2329785T3 (fr)
HK (1) HK1049483B (fr)
HR (1) HRP20020574B1 (fr)
HU (1) HUP0203677A2 (fr)
IL (2) IL149289A0 (fr)
IS (1) IS2191B (fr)
MX (1) MXPA02005602A (fr)
NO (1) NO323544B1 (fr)
NZ (1) NZ518722A (fr)
PL (1) PL364922A1 (fr)
SK (1) SK7982002A3 (fr)
UA (1) UA73543C2 (fr)
WO (1) WO2001042213A1 (fr)
YU (1) YU42402A (fr)
ZA (2) ZA200204557B (fr)

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA73543C2 (uk) * 1999-12-07 2005-08-15 Тераванс, Інк. Похідні сечовини, фармацевтична композиція та застосування похідного при приготуванні лікарського засобу для лікування захворювання, яке опосередковується мускариновим рецептором
GB0108099D0 (en) * 2001-03-30 2001-05-23 Hoffmann La Roche Aminopiperidine derivatives
US20030236287A1 (en) * 2002-05-03 2003-12-25 Piotrowski David W. Positive allosteric modulators of the nicotinic acetylcholine receptor
EA200500173A1 (ru) 2002-07-08 2005-08-25 Рэнбакси Лабораториз Лимитед Производные 3,6-дизамещенного азабицикло[3.1.0]гексана в качестве антагонистов мускариновых рецепторов
TW200800953A (en) * 2002-10-30 2008-01-01 Theravance Inc Intermediates for preparing substituted 4-amino-1-(pyridylmethyl) piperidine
CN100364990C (zh) * 2002-10-30 2008-01-30 施万制药 取代的4-氨基-1-(吡啶甲基)哌啶和相关化合物
PE20040950A1 (es) * 2003-02-14 2005-01-01 Theravance Inc DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS
CN101239969B (zh) * 2003-02-14 2011-07-20 施万制药 联苯衍生物
EP1608319A4 (fr) 2003-04-03 2007-02-28 Univ California Inhibiteurs ameliores pour hydrolase epoxyde soluble
US7517905B2 (en) 2003-04-09 2009-04-14 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists
EP1626957A1 (fr) 2003-04-11 2006-02-22 Ranbaxy Laboratories Limited Derives azabicyclo utiles comme antagonistes du recepteur muscarinique
CA2530376A1 (fr) * 2003-06-23 2005-01-06 Cv Therapeutics, Inc. Derives d'uree de piperazines et de piperidines comme inhibiteurs de l'oxydation d'acides gras
WO2005007645A1 (fr) * 2003-07-11 2005-01-27 Theravance, Inc. Composes de 4-amino-1-benzylpiperidine substitues
AR047759A1 (es) * 2003-09-26 2006-02-22 Vertex Pharma Derivados de fenil - piperazina como moduladores de receptores muscarnicos
PE20050973A1 (es) * 2003-10-29 2005-11-19 Theravance Inc Sales de acido naftalen-1,5-disulfonico de un compuesto de 4-amino-1-(piridilmetil)piperidina como antagonistas de receptores muscarinicos
CA2543858C (fr) * 2003-11-21 2014-04-15 Theravance, Inc. Composes ayant une activite agoniste de recepteur adrenergique beta 2 et antagoniste de recepteur muscarinique
US7320990B2 (en) 2004-02-13 2008-01-22 Theravance, Inc. Crystalline form of a biphenyl compound
US7456199B2 (en) * 2004-03-11 2008-11-25 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
TWI341836B (en) 2004-03-11 2011-05-11 Theravance Inc Biphenyl compounds useful as muscarinic receptor antagonists
WO2005087733A1 (fr) * 2004-03-11 2005-09-22 Theravance, Inc. Composes biphenyle utiles comme antagonistes du recepteur muscarinique
JP2007528415A (ja) * 2004-03-11 2007-10-11 セラヴァンス， インコーポレーテッド ムスカリンレセプターアンタゴニストとしての有用なビフェニル化合物
JP2007528413A (ja) * 2004-03-11 2007-10-11 セラヴァンス， インコーポレーテッド ムスカリンレセプターアンタゴニストとしての有用なビフェニル化合物
US7262205B2 (en) * 2004-03-11 2007-08-28 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
EP1723115A1 (fr) * 2004-03-11 2006-11-22 Theravance, Inc. Composes de biphenyle utiles comme antagonistes du recepteur muscarinique
TW200538095A (en) * 2004-03-11 2005-12-01 Theravance Inc Biphenyl compounds useful as muscarinic receptor antagonists
JP2007532484A (ja) 2004-03-16 2007-11-15 ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア 可溶性エポキシド加水分解酵素の阻害剤およびエポキシエイコサノイドを用いて腎症を緩和する方法
WO2005112988A2 (fr) * 2004-05-21 2005-12-01 The Regents Of The University Of California Procedes pour traiter et diagnostiquer le cancer au moyen du facteur inhibiteur de wnt 1 (wif-1)
US7569586B2 (en) * 2004-08-16 2009-08-04 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7528253B2 (en) * 2004-08-16 2009-05-05 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
TWI374883B (en) 2004-08-16 2012-10-21 Theravance Inc Crystalline form of a biphenyl compound
CA2584342C (fr) 2004-10-20 2013-04-30 The Regents Of The University Of California Inhibiteurs ameliores de l'epoxyde hydrolase soluble
US7880007B2 (en) 2004-11-29 2011-02-01 Vertex Pharmaceuticals Incorporated Bicyclic substituted phenyl piperidine modulators of muscarinic receptors
GB0503054D0 (en) * 2005-02-14 2005-03-23 Smithkline Beecham Corp Chemical compounds
WO2006099031A1 (fr) * 2005-03-10 2006-09-21 Theravance, Inc. Composes biphenyles utiles en tant qu'antagonistes des recepteurs muscariniques
EP1856112A1 (fr) * 2005-03-10 2007-11-21 Theravance, Inc. Composes de biphenyle utilises comme antagonistes des recepteurs muscariniques
EP1866284A1 (fr) * 2005-03-10 2007-12-19 Theravance, Inc. Composes biphenyles utiles en tant qu'antagonistes des recepteurs muscariniques
US7659403B2 (en) * 2005-03-10 2010-02-09 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
TWI372749B (en) * 2005-03-10 2012-09-21 Theravance Inc Crystalline forms of a biphenyl compound
TW200714587A (en) * 2005-03-10 2007-04-16 Theravance Inc Biphenyl compounds useful as muscarinic receptor antagonists
US7786308B2 (en) * 2005-03-28 2010-08-31 Vertex Pharmaceuticals Incorporated Muscarinic modulators
WO2006138218A1 (fr) * 2005-06-13 2006-12-28 Theravance, Inc. Composes de biphenyle utilises comme inhibiteurs des recepteurs muscariniques
US8429052B2 (en) * 2005-07-19 2013-04-23 Lincoln National Life Insurance Company Method and system for providing employer-sponsored retirement plan
WO2007045979A1 (fr) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions pharmaceutiques d'antagonistes du recepteur muscarinique
GB0602778D0 (en) 2006-02-10 2006-03-22 Glaxo Group Ltd Novel compound
US7973055B2 (en) * 2006-03-09 2011-07-05 Theravance, Inc. Crystalline forms of a biphenyl compound
TW200808723A (en) * 2006-03-13 2008-02-16 Univ California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
WO2008096870A1 (fr) * 2007-02-09 2008-08-14 Astellas Pharma Inc. Composé à cycle à pont aza
EP2222637A1 (fr) * 2007-12-14 2010-09-01 Theravance, Inc. Composés contenant de l'amidine utiles comme antagonistes du récepteur muscarinique
EP2096105A1 (fr) * 2008-02-28 2009-09-02 Laboratorios Almirall, S.A. Dérivés de 4-(2-amino-1-hydroxyethyl)phénol en tant qu'antagonistes du récepteur adrénergique b2
DK3210981T3 (en) 2009-04-23 2019-04-01 Theravance Respiratory Co Llc DIAMIDE COMPOUNDS WITH MUSCARINE RECEPTOR ANTAGONIST AND BETA-2 ADDRESSER RECEPTOR AGONIST ACTIVITY
EP2528604B1 (fr) 2010-01-29 2017-11-22 The Regents of the University of California Inhibiteurs d'acyl pipéridine d'époxyde hydrolase soluble
RU2013118026A (ru) * 2010-10-20 2014-10-27 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Карбонатные производные для лечения кашля
JP6021616B2 (ja) * 2012-12-04 2016-11-09 株式会社アエタスファルマ ３−ピペラジニル−１−ピペリジニル−プロパン誘導体及びそれを含有してなる医薬組成物
KR101514320B1 (ko) 2013-06-14 2015-04-22 재단법인 의약바이오컨버젼스연구단 신규한 암 예방 또는 치료용 약학적 조성물
SI3153511T1 (sl) * 2014-06-06 2019-08-30 Astellas Pharma Inc. Derivat 2-acilaminotiazola za uporabo v preprečevanju ali zdravljenju bolezni mehurja/urinarnega trakta
WO2020086864A1 (fr) * 2018-10-24 2020-04-30 Vanderbilt University Modulateurs allostériques positifs du récepteur d'acétylcholine muscarinique m1
WO2020204548A1 (fr) * 2019-03-29 2020-10-08 재단법인 의약바이오컨버젼스연구단 Nouveau composé ayant une activité anticancéreuse, et procédé de production associé

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4587046A (en) 1982-05-18 1986-05-06 The Regents Of The University Of California Drug-carrier conjugates
DE3402060A1 (de) 1984-01-21 1985-08-01 Dr. Karl Thomae Gmbh, 7950 Biberach Substituierte 5,11-dihydro-6h-dibenz(b,e)azepin-6-one, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
US4675326A (en) 1985-05-08 1987-06-23 Gabriel Amitai Bisquaternary antidotes
DK443489D0 (da) * 1989-09-08 1989-09-08 Ferrosan As Substituerede urinstofforbindelser, deres fremstilling og anvendelse
EP0640081B1 (fr) * 1992-03-31 2000-01-12 Glaxo Group Limited Phenylurees et phenylcarbamates substitues, leur preparation, et leur utilisation comme antagonistes de 5-ht4
CA2123728A1 (fr) * 1993-05-21 1994-11-22 Noriyoshi Sueda Derives de l'uree et leur utilisation comme inhibiteurs de l'acat
AU7545894A (en) * 1993-09-02 1995-03-22 Yamanouchi Pharmaceutical Co., Ltd. Carbamate derivative and medicine containing the same
KR970701174A (ko) * 1994-02-10 1997-03-17 오노다 마사요시 신규한 카바메이트 유도체 및 이의 의약 조성물(Novel carbamate derivative and medicinal composition containing the same)
US5691323A (en) 1995-05-12 1997-11-25 Merck & Co., Inc. Muscarine antagonists
EP0863141B1 (fr) * 1995-10-13 2001-09-12 Banyu Pharmaceutical Co., Ltd. Derives heteroaromatiques substitues
WO1998000141A1 (fr) * 1996-07-01 1998-01-08 Sepracor, Inc. Procedes et compositions de traitement de l'incontinence urinaire par (s)-trihexyphenidyle enrichi en enantiomere
US6500934B1 (en) 1996-07-24 2002-12-31 Michael Rush Lerner Bivalent agonists for G-protein coupled receptors
PE92198A1 (es) 1996-08-01 1999-01-09 Banyu Pharma Co Ltd Derivados de 1,4-piperidina disustituida que contienen fluor
US6062766A (en) * 1997-08-04 2000-05-16 Quixote Corporation Raised pavement marker
JP2002508366A (ja) * 1997-12-12 2002-03-19 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー キノリンピペラジンおよびキノリンピペリジン誘導体、それらの製造方法、ならびに複合的５−ｈｔ１ａ、５−ｈｔ１ｂおよび５−ｈｔ１ｄ受容体アンタゴニストとしてのそれらの用途
US6086881A (en) * 1998-05-15 2000-07-11 Children's Medical Center Corp. Spatially aligned conjugated composition having a thioether bond linkage
US6066636A (en) * 1998-06-30 2000-05-23 Schering Corporation Muscarinic antagonists
UA73543C2 (uk) * 1999-12-07 2005-08-15 Тераванс, Інк. Похідні сечовини, фармацевтична композиція та застосування похідного при приготуванні лікарського засобу для лікування захворювання, яке опосередковується мускариновим рецептором
US7238709B2 (en) * 1999-12-07 2007-07-03 Theravance, Inc. Therapeutic carbamates
WO2001098458A2 (fr) * 2000-06-19 2001-12-27 Zyomyx, Inc. Procédés permettant d'immobiliser des polypeptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0142213A1 *

Also Published As

Publication number Publication date
EP1457488B1 (fr) 2009-08-12
EA200200646A1 (ru) 2002-12-26
HRP20020574B1 (en) 2007-12-31
NO20022683L (no) 2002-07-02
US20040054187A1 (en) 2004-03-18
BR0015963A (pt) 2002-08-06
AU782232B2 (en) 2005-07-14
US20020049195A1 (en) 2002-04-25
IS2191B (is) 2007-01-15
YU42402A (sh) 2006-01-16
IL149289A (en) 2007-05-15
KR100748150B1 (ko) 2007-08-09
HRP20020574A2 (en) 2005-08-31
ES2329785T3 (es) 2009-12-01
CN1271054C (zh) 2006-08-23
DE60042762D1 (de) 2009-09-24
IS6362A (is) 2002-04-26
IL149289A0 (en) 2002-11-10
PL364922A1 (en) 2004-12-27
HK1049483A1 (en) 2003-05-16
EA006437B1 (ru) 2005-12-29
HK1049483B (zh) 2005-02-18
AU1951801A (en) 2001-06-18
EP1235803B1 (fr) 2004-07-14
ZA200204557B (en) 2003-09-08
UA73543C2 (uk) 2005-08-15
JP2003516391A (ja) 2003-05-13
US6635764B2 (en) 2003-10-21
NO323544B1 (no) 2007-06-11
CA2392030A1 (fr) 2001-06-14
ZA200204553B (en) 2003-09-08
ES2225275T3 (es) 2005-03-16
CZ20021830A3 (cs) 2002-10-16
NZ518722A (en) 2004-03-26
CA2392030C (fr) 2009-08-18
WO2001042213A1 (fr) 2001-06-14
HUP0203677A2 (hu) 2003-03-28
CN1407970A (zh) 2003-04-02
SK7982002A3 (en) 2002-12-03
ATE439345T1 (de) 2009-08-15
MXPA02005602A (es) 2004-09-10
DE60012223T2 (de) 2005-08-25
KR20020058083A (ko) 2002-07-12
ATE271039T1 (de) 2004-07-15
ES2243333T3 (es) 2005-12-01
EP1457488A1 (fr) 2004-09-15
DE60012223D1 (de) 2004-08-19
US20040116706A1 (en) 2004-06-17
NO20022683D0 (no) 2002-06-06

Similar Documents

Publication Publication Date Title
EP1235803B1 (fr) Composes d'uree presentant une activite antagoniste du recepteur muscarinique
EP1235802B1 (fr) Derives de carbamate presentant une activite antagoniste du recepteur muscarinique
US6693202B1 (en) Muscarinic receptor antagonists
AU763638B2 (en) Muscarinic receptor antagonists
CA2319751A1 (fr) Agonistes polyvalents, agonistes partiels, agonistes inverses et antagonistes des recepteurs 5ht2

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020618

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: OARE, DAVID

Inventor name: MAMMEN, MATHAI

17Q First examination report despatched

Effective date: 20030410

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 60012223

Country of ref document: DE

Date of ref document: 20040819

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: E. BLUM & CO. PATENTANWAELTE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041207

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041207

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20040714

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041231

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1049483

Country of ref document: HK

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2225275

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20050415

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: THERAVANCE, INC.

Free format text: THERAVANCE, INC.#901 GATEWAY BOULEVARD#SOUTH SAN FRANCISCO, CA 94080 (US) -TRANSFER TO- THERAVANCE, INC.#901 GATEWAY BOULEVARD#SOUTH SAN FRANCISCO, CA 94080 (US)

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041214

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60012223

Country of ref document: DE

Representative=s name: MEISSNER, BOLTE & PARTNER GBR, DE

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60012223

Country of ref document: DE

Representative=s name: MEISSNER BOLTE PATENTANWAELTE RECHTSANWAELTE P, DE

Effective date: 20141202

Ref country code: DE

Ref legal event code: R082

Ref document number: 60012223

Country of ref document: DE

Representative=s name: MEISSNER, BOLTE & PARTNER GBR, DE

Effective date: 20141202

Ref country code: DE

Ref legal event code: R081

Ref document number: 60012223

Country of ref document: DE

Owner name: THERAVANCE BIOPHARMA R&D IP, LLC (N.D.GES.D. S, US

Free format text: FORMER OWNER: THERAVANCE, INC., SOUTH SAN FRANCISCO, CALIF., US

Effective date: 20141202

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Owner name: THERAVANCE BIOPHARMA R&D IP, LLC, US

Effective date: 20150123

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20150528 AND 20150603

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOHEST AG, CH

Ref country code: CH

Ref legal event code: PUE

Owner name: THERAVANCE BIOPHARMA R&D IP, LLC, US

Free format text: FORMER OWNER: THERAVANCE, INC., US

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: THERAVANCE BIOPHARMA R&D IP, LLC.

Effective date: 20151116

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151207

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151207

PGRI Patent reinstated in contracting state [announced from national office to epo]

Ref country code: IT

Effective date: 20170710

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20191226

Year of fee payment: 20

Ref country code: IT

Payment date: 20191219

Year of fee payment: 20

Ref country code: BE

Payment date: 20191227

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20200102

Year of fee payment: 20

Ref country code: DE

Payment date: 20191231

Year of fee payment: 20

Ref country code: GB

Payment date: 20200102

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20191231

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60012223

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20201206

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20201206

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20201207

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20210730

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20201208